生理和间歇低氧时Orexin和组胺对舌下神经运动神经元调控作用的机制研究

Obstructive sleep apnea hypopnea syndrom (OSAHS) is a high incidence and hazard of systemic disease, morbidity associated with upper airway obstruction or collapse. The hypoglossal motor nucleus innervates intrinsic and extrinsic tongue muscles including genioglossus. Decreased activity of these muscles contributes to increased upper airway resistance and the predisposition to airway occlusion in sleep. Our previous research indicate that orexin and histaminergic system are involved in regulation of HMN. However, the molecular mechanisms underlying the modulation of hypoglossal motoneurons across sleep–wake states by orexin and histaminergic system are not clear. In this proposal, we will use novel techniques of Cre-flox, DREADD, Patch Clamp and electrophysiological in vitro to clarify the molecular roles of orexin and histaminergic system in sleep-wake regulation of HMN and genioglossus. Significance of this study not only lies in a better understanding of pathological mechanisms of OSA, but also provides neurophysiology strategies for pharmacological attempts to increase pharyngeal muscle tone in sleep to prevent obstructive sleep apnea.

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是一种发病率高、危害大的全身性疾病，发病与上气道塌陷有关。舌下神经运动神经元（HMNs）控制颏舌肌等上气道肌群，其活性与OSAHS发病密切相关。我们发现orexin和组胺能神经元在HMNs的活性调控中发挥重要作用，但机制不明。我们假设orexin和组胺能神经元与HMNs存在交互调控，颏舌肌张力下降致上气道塌陷、间歇低氧，激活HMNs，再活化Orexin与组胺能神经，引发觉醒。本课题拟用电生理、光遗传学及“DREADD”、神经投射追踪、免疫组化、动物模型等方法，研究HMNs调控颏舌肌活性及内源性orexin和组胺调控HMNs活性的机制、orexin和组胺能神经与HMNs相互作用的神经环路。结果将揭示在生理和间歇低氧时Orexin和组胺能神经元调控HMNs的机制，有助于从中枢层面阐明OSAHS的发病机制，为发现OSAHS药物治疗的重要靶点提供新思路。

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是一种发病率高、危害大的全身性疾病，发病与上气道塌陷有关。舌下神经运动神经元（HMNs）控制颏舌肌等上气道肌群，其活性与OSAHS发病密切相关。我们发现orexin和组胺能神经元在HMNs的活性调控中发挥重要作用，但机制不明。本课题利用膜片钳技术证实了组胺对舌下运动神经核的调控作用，并挖掘了具体的分子机制，同时证实了在间歇低氧条件下，舌下运动神经核的兴奋性降低，颏舌肌肌电下降，提高脑内组胺递质浓度，无论常氧还是间歇低氧条件下，均能上调舌下运动神经核兴奋性，引起颏舌肌肌电上升，抑制脑内orexin与受体结合发挥作用时，常氧和间歇低氧条件下，舌下运动神经核的兴奋性均下降，颏舌肌肌电降低，因此本课题有助于从中枢层面阐明OSAHS的发病机制，为发现OSAHS药物治疗的重要靶点提供新思路。